mRNA and gene editing: Late breaking therapies in liver diseases

Abstract

The efficient delivery of RNA molecules to restore the expression of a missing or inadequately functioning protein in a target cell and the intentional specific modification of the host genome using engineered nucleases represent therapeutic concepts that are revolutionizing modern medicine. The initiation of several clinical trials using these approaches to treat metabolic liver disorders as well as the recently reported remarkable results obtained by patients with transthyretin amyloidosis highlight the advances in this field and show the potential of these therapies to treat these diseases safely and efficaciously. These advances have been possible due, firstly, to significant improvements made in RNA chemistry that increase its stability and prevent activation of the innate immune response and, secondly, to the development of very efficient liver-targeted RNA delivery systems. In parallel, the breakout of CRISPR/CRISPR-associated 9-based technology in the gene editing field has marked a turning point in in vivo modification of the cellular genome with therapeutic purposes, which can be based on gene supplementation, correction, or silencing. In the coming years we are likely to witness the therapeutic potential of these two strategies both separately and in combination. In this review we summarize the preclinical data obtained in animal models treated with mRNA as a therapeutic agent and discuss the different gene editing strategies applied to the treatment of liver diseases, highlighting both their therapeutic efficacy as well as safety concerns.

FIGURE 1

Representation of three of the vehicles employed to deliver mRNA to the liver: (A) MTx‐LNPs, (B) hybrid delivery system hybrid mRNA technology (HMT) comprising a polymer micelle for hepatocyte‐specific delivery and endosomal escape and an inert LNP that protects the mRNA, (C) TT‐lipid containing LNPs. A, B, and C LNPs are endocytosed by the hepatocytes; once in the cytoplasm of the cell, the mRNAs are released from endosomes to cytoplasm, where they are translated into proteins that localize in different cellular compartments according to their nature. Abbreviations: DMG‐PEG, 1,2‐dimyristoyl‐rac‐glycero‐3‐methoxy‐PEG 2000; GalNAc, N‐acetylgalactosamine

FIGURE 2

Different gene editing approaches for the treatment of liver diseases. Gene insertion into the albumin locus by spontaneous homologous direct recombination or after the introduction of DSBs in the albumin locus using ZFN nucleases. Gene correction by homologous recombination in the target gene, DNA template provided by an AAV. CRISPR/Cas9‐mediated indel formation and gene silencing after the introduction of DSBs and NHEJ. Base editing for the correction of a specific mutation for the expression of a correct version of the protein. Correction of genetic mutation by PE